C5a
C5a is cleaved from C5 upon complement activation. Among the complement activation products, C5a is one of the most potent inflammatory peptides, with a broad spectrum of functions (Guo R F, and Ward P A. 2005. Annu. Rev. Immunol. 23:821-852). C5a is a glycoprotein present in the blood of healthy humans with a molecular weight of 11.2 kDa. The polypeptide portion of C5a contains 74 amino acids, accounting for a molecular weight of 8.2 kDa while the carbohydrate portion accounts for approximately 3 kDa. C5a exerts its effects through the high-affinity C5a receptors (C5aR and C5L2) (Ward P A. 2009. J. Mol. Med. 87(4):375-378). C5aR belongs to the rhodopsin-type family of G-protein-coupled receptors with seven transmembrane segments; C5L2 is similar but is not G-protein-coupled. It is currently believed that C5a exerts its biological functions primarily through C5a-C5aR interaction, as few biological responses have been found for C5a-C5L2 interaction. C5aR is widely expressed on myeloid cells including neutrophils, eosinophils, basophils, and monocytes, and non-myeloid cells in many organs, especially in the lung and liver, indicative of the importance of C5a/C5aR signaling. C5a has a variety of biological functions (Guo and Ward, 2005, supra). C5a is a strong chemoattractant for neutrophils and also has chemotactic activity for monocytes and macrophages. C5a causes an oxidative burst (O2 consumption) in neutrophils and enhances phagocytosis and release of granular enzymes. C5a has also been found to be a vasodilator. C5a has been shown to be involved in modulation of cytokine expression from various cell types, to enhance expression of adhesion molecules on neutrophils. It is found that C5a becomes highly detrimental when it is overly produced in the disease settings, as it is a strong inducer and enhancer for inflammatory responses functioning in the up-stream of the inflammatory reaction chain. High doses of C5a can lead to nonspecific chemotactic “desensitization” for neutrophils, thereby causing broad dysfunction (Huber-Lang M et al. 2001. J. Immunol. 166(2):1193-1199).
C5a has been reported to exert numerous pro-inflammatory responses. For example, C5a stimulates the synthesis and release from human leukocytes of pro-inflammatory cytokines such as TNF-α, IL-1β, IL-6, IL-8, and macrophage migration inhibitory factor (MIF) (Hopken U et al. 1996. Eur J Immunol 26(5):1103-1109; Riedemann N C et al. 2004. J Immunol 173(2):1355-1359; Strieter R M et al. 1992. Am J Pathol 141(2):397-407). C5a produces a strong synergistic effect with LPS in production of TNF-α, macrophage inflammatory protein (MIP)-2, cytokine-induced neutrophil chemoattractant (CINC)-1, and IL-1β in alveolar epithelial cells (Riedemann N C et al. 2002. J. Immunol. 168(4):1919-1925; Rittirsch D et al. 2008. Nat Rev Immunol 8(10):776-787).
Blockade of C5a has also been proven to be protective in experimental models of sepsis and in many other models of inflammation such as ischemia/reperfusion injury, renal disease, graft rejection, malaria, rheumatoid arthritis, infectious bowel disease, inflammatory lung disease, lupus-like auto-immune diseases, neurodegenerative disease, etc. in various species as partially reviewed under Klos A. et al (Klos A. et al. 2009. Mol Immunol 46(14):2753-2766) and Allegretti M. et al (Allegretti M et al. 2005. Curr Med Chem 12(2):217-236). Moreover, it has been recently discovered that blockade of C5a has shown a strong therapeutic benefit in a tumor model in mice (Markiewski M M et al. 2008. Nat Immunol 9(11): 1225-1235).
Avian Influenza
A novel avian influenza H7N9 virus emerged in China in February 2013 and a total of 139 patients with 45 fatal cases were confirmed till November 2013 (WHO. Human infection with avian influenza A(H7N9) virus—update. http://www.who.int/csr/don/2013_11_06/en/index.html (accessed on Nov. 16, 2013)). Most severe cases infected with H7N9 viral infection had manifestation of viral pneumonia with acute lung injury (ALI) and then progressed to severe respiratory failure and acute respiratory distress syndrome (ARDS) which was similar to the pathogenesis in patients infected with HPAI (highly pathogenic avian influenza) H5N1 virus or severe acute respiratory syndrome (SARS) virus (Beigel J H et al. 2005. N Engl J Med 353:1374-1385; Ip W K, et al. 2005. J Infect Dis 191:1697-1704). To date, no therapeutic strategies have been found to effectively treat these diseases. Accumulating studies suggested that the complement activation occurred in severe patients infected with influenza virus and was closely associated with the levels of proinflammatory mediators and lung injury. It has been reported that patients with severe pdmH1NI (pandemic influenza H1N1) virus infection had strong systemic complement activation with increased production of proinflammatory mediators (Berdal J E et al. 2011. J. Infect. 63(4):308-16; Ohta R et al. 2011. Microbiol. Immunol. 55(3):191-8). In addition, our previous studies have showed that the complement activation products in lung tissue sections and plasma samples were largely increased in the mouse model of H5N1 infection, and that the pathogenesis of ALI could be attributable, at least in part, to the complement activation and associated activation products such as C3a and C5a (Sun, S. et al. 2013. Am J Respir Cell Mol Biol 49: 221-230).
Complement system is a central part of the immune system in host defenses against pathogen invasion and in clearance of potentially damaging cell debris. However, excessive complement activation could be detrimental, since it may contribute to uncontrolled inflammatory responses and lead to tissue damages (Daniel Ricklin & John D Lambris. 2013 J Immunol 190(8):3831-8). Complement has become an interesting and promising target for treatment of various clinical diseases such as ischemia/reperfusion (I/R) injury, transplantation and autoimmune disorders (Lu F. et al. 2013. Cardiovasc. Pathol. 22:75-80; Tillou, X. et al. 2010. Kidney Int. 78:152-159; Manderson A P, et al. 2004. Annu Rev Immunol 22:431-456. Since the role of complement activation in the outcome of pathogen-induced diseases could be more complex due to the diversity of pathogen biological features including propagation and pathogenicity as well as a potential “dual role” of complement activation in the pathogen-driven immune responses, it is important to consider preservation of pathogen clearance function while inhibiting inflammation and tissue injury for the development of complement inhibitors for the treatment of pathogen-associated inflammatory disorders.
Complement activation product C5a exerts a predominant proinflammatory activity and mediates strong proinflammatory and modulatory signals in many disease models (Klos A. et al. 2009, supra). To date, many therapeutic compounds targeting C5a or C5aR such as C5a inhibitor C5aIP, C5aR antagonist PMX53 and CCX168 had been tested in the preclinical models with promising therapeutic benefits in transplantation, sepsis, arthritis, renal vasculitis and cancer (Woodruff, T. M. et al. 2011. Mol. Immunol. 48:1631-1642; Okada, N. et al. 2012. Clin. Exp. Pharmacol. 2:114; Tokodai, K. et al. 2010. Transplantation 90:1358-1365; Köhl, J. 2006. Curr. Opin. Mol. Ther. 8: 529-538). It was also demonstrated that antibody blockade of C5a or C5a receptor abrogated the excessive immune responses in the mouse model of Plasmodium berghei ANKA (PbA) infection (Patel, S. N. et al. 2008. J. Exp. Med. 205:1133-1143). Similarly, our previous study employing a mouse model of HPAI H5N1 viral pneumonia revealed that anti-C5a treatment significantly attenuated lung injury and improved the survival rate (Sun, S. et al. 2013, supra). Since membrane attack complex (MAC) plays an essential role in the innate host defenses again invading pathogens, it appears to be advantageous to apply C5a blockade strategy inhibiting the inflammatory responses derived from pathogen infection while leaving the arm of MAC formation intact.